Ipilimumab and Hypofractionated Stereotactic Body Radiation Therapy in Treating Patients with Advanced Solid Malignancies
This randomized phase I/II trial studies the side effects and best dose of hypofractionated stereotactic body radiation therapy when given together with ipilimumab in treating patients with solid malignancies that have spread to other places in the body and usually cannot be cured or controlled with treatment. Monoclonal antibodies, such as ipilimumab, may block tumor growth in different ways by targeting certain cells. Hypofractionated radiation is a radiation treatment in which the total dose of radiation is divided into large doses and treatments are given over a shorter period of time. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving ipilimumab with hypofractionated stereotactic body radiation therapy may be a better treatment for advanced solid malignancies.
Inclusion Criteria
- Patients must have histological confirmation of metastatic cancer with at least one metastatic or primary lesion in the liver, lung, or adrenal gland
- Patients who have completed previous systemic therapies 5 drug half-lives or 4-weeks prior to enrollment on study, whichever is shorter; Note: patients with anaplastic thyroid will be waived from this inclusion criteria
- All patients must have at least one metastatic or primary lesion within the lung or liver located in an anatomical location amenable to SBRT treatment with 50 Gy in 4 fractions, or if not, with either a lung, liver, or adrenal lesion treatable to 60 Gy in 10 fractions
- Repeat radiation in fields previously radiated will be allowed at the discretion of the treating physician
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky > 60%)
- Total bilirubin =< 2.0 mg/dL; (does NOT apply to patients with Gilbert’s syndrome)
- Aminotransferase (aspartate aminotransferase [AST]) serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT) < 2.5 x institutional upper limit of normal (patients with liver involvement will be allowed =< 5.0 x institutional upper normal limit)
- White blood cells (WBC) >= 2500/uL
- Absolute neutrophil count (ANC) >= 1000/uL
- Platelets >= 75 K
- Hemoglobin >= 9 g/dL
- Creatinine =< 2.0 x upper limit of normal (ULN)
- Patients must be willing and able to review, understand, and provide written consent before starting therapy
- Patients with brain metastasis will be included as long as they are free of neurologic symptoms related to metastatic brain lesions and who do not require or receive systemic corticosteroid therapy in the 14 days prior to beginning ipilimumab therapy
- Patients that have previously progressed on immunotherapy such as ipilimumab will be eligible
Exclusion Criteria
- Serious autoimmune disease at the discretion of the treating attending: patients with a history of active serious inflammatory bowel disease (including Crohn’s disease and ulcerative colitis) and autoimmune disorders such as rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus or autoimmune vasculitis (e.g., Wegener’s granulomatosis) are excluded from this study
- Active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, abdominal carcinomatosis or other known risk factors for bowel perforation
- Any underlying medical or psychiatric condition, which in the opinion of the investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events: (AE's) e.g. a condition associated with frequent diarrhea or chronic skin conditions, recent surgery or colonic biopsy from which the patient has not recovered, or partial endocrine organ deficiencies
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, history of congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Known active human immunodeficiency virus (HIV), hepatitis B, or hepatitis C that has not been documented to be cured
- Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to one month prior to or after any dose of ipilimumab)
- Concomitant therapy with any of the following: interleukin (IL)-2, interferon or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigational therapies; or chronic use of systemic corticosteroids while receiving ipilimumab (as long as steroid replacement is significantly greater than what is required for physiologic replacement, i.e. in hypothyroidism)
- Pregnant women are excluded from this study; women of child-bearing potential and men must agree to use contraception prior to study entry and for the duration of study participation; acceptable forms of birth control include: birth control pills plus a barrier method, such as a condom or diaphragm, intrauterine devices (IUD) plus a barrier method, implantable or injectable birth control (such as NorplantR or epo-ProveraR) started at least 3 months before joining the study, plus a barrier method, or double-barrier method, such as a condom when used in combination with a diaphragm; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician
- History of or current immunodeficiency disease or prior treatment compromising immune function at the discretion of the treating physician
- Prior allogeneic stem cell transplantation
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02239900.
PRIMARY OBJECTIVES:
I. To evaluate the safety and toxicity profile of intravenous ipilimumab (3 mg/kg, Yervoy) administered in combination with stereotactic body radiation therapy (SBRT) targeting 1-4 liver lesion(s) for patients with metastatic cancers.
II. To evaluate the safety and toxicity profile of intravenous ipilimumab (3 mg/kg, Yervoy) administered in combination with stereotactic body radiation therapy (SBRT) targeting 1-4 lung lesion(s) for patients with metastatic cancer.
III. To evaluate the safety and toxicity profile of intravenous ipilimumab (3 mg/kg, Yervoy) administered in combination with stereotactic body radiation therapy (SBRT) targeting 1 adrenal lesion for patients with metastatic cancer.
IV. To determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of ipilimumab (3 mg/kg) and SBRT (adjustable dose) combination therapy.
SECONDARY OBJECTIVES:
I. To determine antitumor activity of ipilimumab therapy with SBRT treatment for 1-4 lung lesions in both the SBRT treated lesion and non-irradiate tumors.
II. To determine antitumor activity of ipilimumab therapy with SBRT treatment for 1-4 liver lesions in both the SBRT treated lesion and non-irradiate tumors.
III. To determine antitumor activity of ipilimumab therapy with SBRT treatment for 1 adrenal lesion in both the SBRT treated lesion and non-irradiate tumors.
IV. To evaluate treatment efficacy comparing different SBRT and ipilimumab treatment regimens (sequential vs. concurrent).
V. To evaluate treatment efficacy comparing different SBRT treatment sites (liver vs lung vs adrenal).
VI. To evaluate treatment efficacy comparing different SBRT treatment sites (50 Gy in 4 fractions or 60 Gy in 6 fractions).
VII. To evaluate the potential predictive potential of tumor-associated and systemic immune biomarkers for therapy effectiveness and toxicity prediction.
VIII. To determine the systemic antitumor activity of ipilimumab therapy with SBRT treatment in patients with thyroid cancer.
IX. To evaluate whether skeletal mass, neutrophil, neutrophil to lymphocyte ratio, and tumor bulk are correlated with clinical outcomes and adverse events.
X. To evaluate whether tumor kinetics in combination with clinical correlates can help determine treatment response.
OUTLINE: This is a phase I dose de-escalation of SBRT followed by a phase II study. Patients with at least 1 liver metastasis treatable with SBRT are randomized to group I or II. Patients with at least 1 lung metastasis treatable with SBRT are randomized to group III or IV. Patients with either 1 liver or lung metastasis not treatable with SBRT at 50 Gy in 4 fractions or an adrenal metastasis are assigned to group V.
GROUP I (CONCURRENT): Patients receive ipilimumab intravenously (IV) over 90 minutes on day 1 and undergo SBRT on days 2-5 (course 1 only). Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
GROUP II (SEQUENTIAL): Patients receive ipilimumab IV over 90 minutes on day 1 and undergo SBRT on days 30-33 for a total of 4 fractions (course 2 only). Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
GROUP III (CONCURRENT): Patients receive ipilimumab IV over 90 minutes on day 1 and undergo SBRT on days 2-5 (course 1 only). Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
GROUP IV (SEQUENTIAL): Patients receive ipilimumab IV over 90 minutes on day 1 and undergo SBRT on days 30-33 for a total of 4 fractions (course 2 only). Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
GROUP V (SEQUENTIAL): Patients receive ipilimumab IV over 90 minutes on day 1 and undergo SBRT on days 30-41 for a total of 10 fractions (course 2 only). Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
THYROID EXPANSION COHORT (SEQUENTIAL): Patients undergo 4, 5 or 10 fractions of SBRT to a liver or lung lesion at the discretion of the treating radiation oncologist with sequential ipilimumab.
In all Groups, beginning 8 weeks after the last course of ipilimumab, patients achieving systemic disease control (stable disease [SD] or partial response [PR], based on immune related-response criteria [ir-RC]), may receive re-induction with ipilimumab for an additional 4 courses and undergo optional radiation therapy during re-induction sequenced with ipilimumab (concurrent vs sequential).
After completion of study treatment, patients are followed up every 1-3 months for up to 6 months and then every 2-4 months thereafter.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationM D Anderson Cancer Center
Principal InvestigatorJames Welsh
- Primary ID2013-0882
- Secondary IDsNCI-2015-00042
- ClinicalTrials.gov IDNCT02239900